Project Summary Schizophrenia is a severe psychiatric disorder associated with tremendous social, personal, and economic burden. Despite decades of research, the pathophysiology of schizophrenia remains elusive. Translational studies of basic neuroscience tasks in patients are critically needed to uncover the mechanisms that contribute to the onset of illness. However, translational studies examining fundamental mechanisms in humans are lacking. We propose to characterize a fundamental mechanism underlying learning and memory?neural habituation?in the early stage of schizophrenia. Habituation?the reduced response to repeated exposures of a stimulus?is the most basic form of memory and has been extensively studied in simple organisms like aplysia. Although habituation is a fundamental process, neural habituation rate varies across healthy individuals and may reflect differences in learning. Learning and memory are among the earliest and most profoundly affected domains, suggesting that the mechanisms underlying memory deficits may be linked with the pathophysiology of illness. We propose that differences in neural habituation are a key mechanism in the pathology of early schizophrenia. We will recruit schizophrenia patients at an early stage of illness, during emergence of psychotic symptoms, to determine whether habituation deficits exist at this critical stage of illness. To directly test whether habituation to repeated stimuli predicts subsequent recognition memory, we will use a novel habituation task specifically designed to build a tiered level of recognition memory for stimuli. To determine the extent of habituation differences in the brain, we will characterize neural habituation and functional connectivity across a comprehensive network of memory regions involved in schizophrenia. We will study habituation of neural response to repeated stimuli using functional magnetic resonance imaging (fMRI). As memory dysfunction is an early indicator of illness, often preceding onset of psychotic symptoms, and contributes to significant disability, clarifying the mechanisms contributing to memory dysfunction in schizophrenia may help improve our understanding of the disease and our ability to intervene in the disease process.